Targeted cancer therapies have produced substantial clinical responses, but most tumors
develop resistance to these drugs. Here, we describe a pharmacogenomic platform that
facilitates rapid discovery of drug combinations that can overcome resistance.We established
cell culture models derived from biopsy samples of lung cancer patients whose disease had
progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic
lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic
analyses and a pharmacological screen. Multiple effective drug combinations were identified.
For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an
ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the
combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an
EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src)
inhibition was effective in several ALK-driven patient-derived models, a result not predicted
by genetic analysis alone.With further refinements, this strategy could help direct therapeutic
choices for individual patients.